Venetoclax and Decitabin Based Conditioning Regimen Followed With Post-HSCT Decitabin Maintenance Therapy in TP53 Mutant AML/MDS Patients

This study aims to evaluate the effectiveness and safety of Venetoclax and Decitabin based conditioning regimen followed with post-HSCT Decitabin maintenance therapy in TP53 mutant AML/MDS Patients.

Study Overview

• Status: Recruiting
• Conditions: Hematopoietic Stem Cell Transplantation; TP53
• Intervention / Treatment: Drug: VEN and DEC based conditioning regimen; Drug: DEC

Detailed Description

In acute myeloid leukemia and myelodysplastic syndromes, TP53 gene mutation is a poor prognostic factor and a strong indication for hematopoietic stem cell transplantation. However, because of the high relapse rate of myeloid tumors with TP53 mutation, new comprehensive treatment is urgently needed to improve the efficacy of transplantation. Decitabin(DEC) has shown certain efficacy in primary patients with TP53 mutation, and Venetoclax (VEN) and DEC have synergistic effect. Based on this, we hypothesized that DEC and VEN should be added to the conditioning regimen in TP53 mutant AML/MDS patients in order to eliminate malignant clones with P53 mutation as much as possible, and intermittent DEC maintenance therapy should be used to prevent relapse after post-HSCT hematopoietic reconstruction. We intend to conduct a multicenter, single-arm clinical study to evaluate the efficacy and safety of this protocol.

• Study Type: Interventional
• Enrollment (Anticipated): 58
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Yanmin Zhao, PhD; Phone Number: +8615858199217; Email: yanminzhao@zju.edu.cn

Study Locations

• China
  • Zhejiang
    • Hangzhou, Zhejiang, China, 310006
      • Recruiting
      • The First Hospital of Zhejiang Medical Colleage Zhejiang University
      • Contact: Yanmin Zhao, PhD; Phone Number: +8615858199217; Email: yanminzhao@zju.edu.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years to 70 years (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. AML or MDS diagnosed according to 2016 WHO criteria with TP53 mutation before enrollment;
2. Aged from 12 to 70 years;
3. The Eastern Cooperative Oncology Group (ECOG) performance score of 0-2;
4. Creatinine clearance rate ≥ 60 mL/min (according to Cockcroft-Gault formula);
5. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≥ 3× upper limit of normal range (ULN), total bilirubin ≤ 2×ULN;
6. Left ventricular ejection fraction (LVEF) assessed by echocardiography (ECHO) ≥ 45%;
7. Life expectancy > 8 weeks;
8. Sign the informed consent voluntarily, understand and comply with all trial requirements.

Exclusion Criteria:

1. Active autoimmune diseases, such as SLE, rheumatoid arthritis, etc.
2. Current active cardiovascular disease with clinically significance, such as uncontrolled arrhythmias, uncontrolled hypertension, congestive heart failure, any grade 3 or 4 heart disease determined by the New York Heart Association (NYHA) functional classification, or a history of myocardial infarction within the 6 months prior to screening;
3. Other serious medical conditions (e.g., advanced infection) that may limit the patient's participation in the trial;
4. Known human immunodeficiency virus (HIV) infection, or drug-uncontrolled chronic infection of hepatitis B virus (HBV-DNA > 1000IU/ml) or hepatitis C virus (anti-HCV positive);
5. Pregnant or lactating women;
6. Fail to understand, comply with the study protocol or sign the informed consent form.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: VEN and DEC based conditioning regimen followed with post-HSCT DEC maintenance therapy

Drug: VEN and DEC based conditioning regimen; Patients with age<50 years and HCT-CI<3: Haploidentical transplantation: AraC 2g/m2 d-10~d-9, BU 0.8mg/kg q6h d-8~-6, CTX 1.8g/m2 d-5~d-4, Meccnu 250mg/m2 d-3, ATG 1.5mg/kg/d d-5~-2, VEN 400mg/d d-15~-9, DEC 20mg/m2 d-15~-11; HLA-matched transplantation: BU 0.8mg/kg q6h d-7~-4, CTX 60mg/kg d-3~d-2, Meccnu 250mg/m2 d-1, VEN d-12~-8, DEC 20mg/m2 d-12~-6, and ATG for the unrelated donor type. Patients with age>50 years or HCT-CI≥3: Flu 30mg/m2 d-10~-5, BU 0.8mg/kg q6h d-7~-5, Meccnu 250mg/m2 d-4, ATG 7.5mg/kg divided into d-4~-1, VEN d-15~-9, DEC 20mg/m2 d-15~-11. Note: if Voriconazole or Posaconazole is used to prevent or treat fungal infections, VEN should be 200mg/d for 7 consecutive days.; Drug: DEC; In the time window of 60-120 days after transplantation: DEC 5mg/m2/d for 5 consecutive days every 6 to 8 weeks with a total of 4 to 6 courses if there is no severe aGVHD (grade 3 or higher) and the donor chimerism rate of bone marrow blood (STR)>95%. If the MRD turns positive, DLI can be performed.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival (PFS)	The time from transplantation to the occurrence of any of the following: Death from any cause; Disease recurrence, defined as one of the following: Leukemia blasts reappeared in peripheral blood, or blasts ≥ 5%, naive monocytes ≥ 5% in bone marrow, or extramedullary lesions.	At Year 1

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival (OS)	Assessment of OS at Year 1	At Year 1
Cumulative relapse rate	Assessment of cumulative relapse rate at Year 1	At Year 1
Non-relapse mortality (NRM)	Assessment of NRM at Year 1	At Year 1
Acute graft-versus-host disease (GVHD)	Acute GVHD incidence	At Day 100
Chronic graft-versus-host disease (GVHD)	Chronic GVHD incidence	through study completion, an average of 1 year
Adverse effects	Drug related adverse effects	through study completion, an average of 1 year

Collaborators and Investigators

• Sponsor: Zhejiang University

Study record dates

Study Major Dates

• Study Start (ACTUAL): June 2, 2022
• Primary Completion (ANTICIPATED): December 31, 2025
• Study Completion (ANTICIPATED): December 31, 2025

Study Registration Dates

• First Submitted: August 28, 2022
• First Submitted That Met QC Criteria: September 2, 2022
• First Posted (ACTUAL): September 6, 2022

Study Record Updates

• Last Update Posted (ACTUAL): September 6, 2022
• Last Update Submitted That Met QC Criteria: September 2, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Keywords: relapse; TP53; hematopoietic stem cell transplantation; decitabine
• Other Study ID Numbers: IIT20220036C-R1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No